DESCRIPTION (provided by principal investigator): Marrow adiposity increases with age and osteoporosis. Although previously thought to function as a neutral filler in the marrow cavity, recent studies suggest that marrow fat accumulation is instead part of dynamic processes that also affect bone density and size. Animal and cell models suggest that marrow adiposity is linked to mesenchymal stem cell (MSC) allocation in the marrow. With aging, MSC allocation favors adipocytes over osteoblasts, leading to reduced bone formation with increased marrow fat. A better understanding of this process in humans could translate into new approaches to bone preservation, promoting MSC allocation towards osteoblasts. Marrow fat may also have direct effects on the bone marrow microenvironment. Similar to other fat depots, marrow fat secretes factors that could potentially affect bone turnover. With non-invasive measurements of marrow fat now possible using magnetic resonance spectroscopy (MRS), small studies have reported correlations between marrow fat and areal bone density by dual energy x-ray absorptiometry (DXA). Studies are needed to characterize associations between marrow fat and bone parameters available with computed tomography (CT), including cortical and trabecular bone density and bone size. In addition, studies are needed to determine if marrow fat is associated with the size of other fat depots to assess whether marrow fat is controlled through mechanisms that are similar or distinct from other fat depots. The effect of bone-active medications on marrow fat can provide additional insight. To address these research questions, we propose a study that will include MRS measurements of vertebral marrow adiposity combined with a full characterization of bone parameters and other fat depots in 300 participants in the Age Gene/Environment Susceptibility-Reykjavik Study (AGES-Reykjavik), a cohort of older adults. As an ancillary study, this research project can take advantage of the already planned CT measurements in AGES-Reykjavik, reducing project costs substantially. This project will determine whether marrow adiposity measured by MRS is associated with cortical and trabecular bone density and bone size at the spine, hip and femoral shaft measured by CT;with areal bone density of the hip and spine from DXA;and with bone turnover markers. Using DXA and CT measurements, the study will determine whether the size of total fat mass, abdominal visceral and subcutaneous fat depots, and the degree of fatty infiltration of muscle at mid-thigh correlate with marrow fat. The study will also evaluate the effect of glucocorticoids, hormone replacement therapy and bisphosphonates on marrow fat in a subset of women (N=45) selected from those who report current use and will assess the associations between marrow fat and fracture risk, including prevalent vertebral fractures and clinical fractures reported during the previous 12 years. This study promises to substantially advance our knowledge of the role of marrow fat in relation to bone and other fat depots, advances that may translate into new therapeutic approaches promoting the osteogenic potential of MSCs. PUBLIC HEALTH RELEVANCE: This study will determine if higher levels of fat in the bone marrow in older adults are associated with reduced bone density and size, and will assess the relationship between marrow fat and other types of body fat, including total and abdominal fat. A better understanding of the process underlying the accumulation of marrow fat with age and osteoporosis may provide new targets for treatments to prevent bone loss.